Pharmaceutical composition comprising paracetamol and niflumic acid

ABSTRACT

A formulation is described comprising paracetamol, niflumic acid or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

This application is a 371 of PCT/EP01/03185 filed Mar. 20, 2001 whichclaims a benefit of UNITED KINGDOM 0006897.3 filed Mar. 23, 2000.

The present invention relates to pharmaceutical compositions containingN-acetyl-p-aminophenol, known by the generic names paracetamol,acetaminophen and APAP (hereinater referred to as paracetamol). Inparticular, the invention relates to a formulation comprisingparacetamol in combination with niflumic acid.

Paracetamol is an analgesic and antipyretic agent which is widely usedin prescription and non-prescription medicines, often in combinationwith other biologically active compounds including non-steroidalanti-inflammatory agents (NSAIDs) such as aspirin, ibuprofen, mefenamicacid or naproxen.

Niflumic acid is a known NSAID, however there has been no suggestion toco-administer it with paracetamol.

It has now been found that a combination of niflumic acid withparacetamol is surprisingly able to increase the maximum analgesiceffect of paracetamol in an established model of pain. This advantageouseffect is not obtained by using alternative NSAMDs such as aspirin,ibuprofen, mefenamic acid or naproxen.

Accordingly, in a first aspect, the present invention provides apharmaceutical composition comprising an effective amount of paracetamoland an effective amount of niflumic acid or a pharmaceuticallyacceptable salt or ester thereof and a pharmaceutically acceptableexcipient.

The paracetamol and niflumic acid or a pharmaceutically acceptable saltor ester thereof may be presented in separate unit dose compositionswhich are suitably adapted for concurrent administration (ie withinabout 5 minutes of each other) and preferably for simultaneousadministration (ie at the same time).

More conveniently the paracetamol and niflumic acid or apharmaceutically acceptable salt or ester thereof are presented togetherin the same unit dose composition, which has the advantage ofsimplifying the dosage regimen and improving patient compliance.

The compositions of this invention are usually adapted for oraladministration, but formulations for parenteral or rectaladministration, or topically applied formulations are also within thescope of this invention.

The composition is usually presented as a unit dose compositioncontaining from 10 to 1000 mg of paracetamol and from 5 to 500 mg ofniflumic acid or a pharmaceutically acceptable salt or ester thereof,more usually from 100 to 800 mg of paracetamol, for example 200 to 600mg of paracetamol, and from 20 to 400 mg of niflumic acid or apharmaceutically acceptable salt or ester thereof, for example from 40to 300 mg of niflumic acid or a pharmaceutically acceptable salt orester thereof. Most preferably unit doses contain from 300 to 500 mg ofparacetamol and from 50 to 250 mg of niflumic acid or a pharmaceuticallyacceptable salt or ester thereof.

Such a composition is normally taken from 1 to 6 times daily, forexample 2, 3 or 4 times daily so that the total daily amountadministered to a patient in need therefore is up to 4000 mg ofparacetamol and up to 1000 mg of niflumic acid or a pharmaceuticallyacceptable salt or ester thereof.

Examples of salts of niflumic acid include alkali metal salts thereof,such as the sodium or potassium salts or amino acid salts thereof, suchas lysine or arginine salts.

A suitable ester of niflumic acid is the 2-morpholinoethyl ester, knownas morniflumate.

In view of the advantageous interaction between paracetamol and niflumicacid or a pharmaceutically acceptable salt or ester thereof, a lowerdose of paracetamol than those conventionally used, can be administeredto obtain the same level of pain relief. This has the advantage that itmay reduce the potential for patients to suffer toxic effects ofparacetamol overdose, which can have fatal consequences or, at the veryleast, lead to irreversible liver damage.

Alternatively, a conventional dose of paracetamol in combination with adose of niflumic acid or a pharmaceutically acceptable salt or esterthereof which is normally considered sub-therapeutic can beadministered, thus reducing the side effects normally associated withNSAIDs.

Alternatively, a more conventional dose of paracetamol in combinationwith niflumic acid or a pharmaceutically acceptable salt or esterthereof, can afford a “power analgesic” able to alleviate more severeforms of acute pain.

The compositions of the present invention, therefore, have usefulanalgesic properties and may be used in the treatment of mild tomoderate pain, or when acting as a “power analgesic” to treat more acuteforms of pain, including migraine.

The compositions of the present invention also have usefulanti-inflammatory properties.

Preferred dosage forms for oral administration includes tablets andcapsules.

Preferred dosage forms for topical application include creams andointments to be applied to the skin.

Preferred dosage forms for rectal application include suppositories.

Suitable excipients for use in this invention include lubricants, forexample magnesium stearate and stearic acid; disintegrants, for examplecellulose derivatives; starches; binders, for example modified starchesand cellulose derivatives; glidants, for example colloidol silicas;compression aids, for example cellulose derivatives; as well aspreservatives, suspending agents, wetting agents, flavouring agents,bulking agents, adhesives, colouring agents, sweetening agentsappropriate to their form. Examples of such excipients are described inthe Handbook of Pharmaceutical Excipients (Second Edition, 1994, editedby A. Wade and P. Weller, published by the American PharmaceuticalAssociation and the Pharmaceutical Press).

In addition to paracetamol, niflumic acid or a pharmaceuticallyacceptable salt or ester thereof and a pharmaceutically acceptableexcipient, formulations of the invention may also contain otherpharmaceutically active agents, for example other analgesics,anti-inflammatory analgesic agents, decongestants, antihistamines,antitussive agents, etc. Formulations may also contain apharmaceutically acceptable analgesic adjuvant, for example caffeine.

The invention also provides a process for the preparation of acomposition of the invention, which process comprises the admixture ofparacetamol and niflumic acid or a pharmaceutically acceptable salt orester thereof together with any pharmaceutically acceptable excipients,additional pharmaceutically acceptable active agents or adjuvants. Thusthe paracetamol and niflumic acid or a pharmaceutically acceptable saltor ester thereof may be mixed together with one or more binders andgranulated using water. The resulting granule may then be dried, sievedand mixed with additional excipients such as a lubricant anddisintegrant before being compressed into tablets. Alternatively, theniflumic acid or a pharmaceutically acceptable salt or ester thereof maybe omitted from the granulation step and subsequently added with theother excipients. In an alternative process, tablets may be preparedusing direct compression grades of paracetamol including commerciallyavailable forms which obviates the need for a granulation step. Tabletsmay also be prepared by other processes known in the art such as byshaping of an extruded mixture. For capsule production, the paracetamoland niflumic acid or a pharmaceutically acceptable salt or ester thereofmay be mixed and granulated as for tablet production and filled intosuitably sized capsule shells to the desired fill weight.

The following Examples illustrate the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of 62.5 mg/kg niflumic acid on the dose-responsecurve for APAP.

FIGS. 2–3 show the effect of 15 mg/kg naproxen on the dose-responsecurve for APAP.

FIG. 4 shows the effect of 37.5 mg/kg aspirin on the dose-response curvefor APAP.

FIG. 5 shows the effect of 75 mg/kg ibuprofen on the dose-response curvefor APAP.

FIG. 6 shows the effect of 30 mg/kg mefenamic acid on the dose-responsecurve for APAP.

EXAMPLE 1 The P-Phenyl-Quinone Induced Mouse Abdominal Constriction(MAC) Assay

The method is based on that described by Siegmund, Cadmus and Lu in “AMethod for Evaluating both Non-Narcotic and Narcotic Analgesics” Proc.Soc. Exp. Biol. Med., 95: 729–731 (1957)).

DBA/2 mice were housed 20 per cage in a temperature and humiditycontrolled environment on a 12:12 hour light-dark cycle for five dayswith food and water ad libitum before testing. A range of doses ofParacetamol (APAP) were tested alone and in combination with niflumicacid, aspirin, ibuprofen, mefenamic acid and naproxen. Ten animals wererandomly allocated to each drug group and experimental designs were usedthat allowed complete randomisation of the testing of drug groups. Drugswere suspended in 1% methylcellulose and administered 10 ml/kg po, 60mins pre-test. Abdominal constriction was induced by i.p. injection of10 ml/kg P-phenyl-quinone (0.025% in 5% ethanol/water) and the totalnumber of constrictions in a twenty minute period were measured. Aconstriction is defined as a flattening of the abdomen with extension ofthe hind limbs. Testing was blind with one experimenter observing fiveanimals. All experiments were performed in accordance with the Animals(Scientific Procedures) Act 1986 and subject to local ethical committeeapproval.

Analysis

For each drug group, the mean % inhibition of constrictions wascalculated ((1-(test/control))*100) and appropriate statistics wereperformed on log-transformed data to test significant differences fromvehicle and, in the case of groups receiving drug combinations, eachdrug alone.

Results

Results are summarised in FIGS. 1 to 6.

-   At all doses of paracetamol, addition of 62.5 mg/kg niflumic acid    increased the % inhibition of constrictions beyond the maximum    effect of paracetamol alone. (FIG. 1)-   This effect was a significant improvement on vehicle and either drug    alone in the groups that received combinations of (i) 50 mg/kg    Paracetamol+62.5 mg/kg Niflumic acid and (ii) 150 mg/kg    Paracetamol+62.5 mg/kg Niflumic acid. At these doses, each drug    alone had a small but significant effect.-   This effect was not seen with naproxen and aspirin at doses with a    similar efficacy to 62.5 mg/kg Niflumic acid (15 mg/kg and 37.5    mg/kg respectively) (FIGS. 2–4)-   The analgesic effect of ibuprofen (75 mg/kg) in combination with    APAP (100 mg/kg) was not significantly greater than the effect of 75    mg/kg ibuprofen alone, suggesting there is no additive interaction    between these two drugs (FIG. 5)-   The analgesic effect of a combination of 30 mg/kg mefenamic acid    with a range of doses of APAP did not elicit a significant advantage    over APAP alone. (FIG. 6)

EXAMPLE 2

A typical tablet of the invention can be prepared as follows:

INGREDIENT mg/tablet g/batch 1. Paracetamol 500 500 2. Niflumic acid 9090 3. PVP 20 20 (polyvinylpyrrolidone) 4. Ac di sol 35 35(Croscarmellose sodium) 5. Magnesium stearate 5 5Method

-   a) Sieve items 1, 2 and 3 through 0.2 mm screen and in a suitable    mixer-   b) Add purified water and mix until a medium density granule has    been achieved-   c) Dry in a tray oven for 2 hours at 50 C.-   d) Sieve the resulting granule through a 0.5 mm screen-   e) Sieve items 4 and 5 through a 0.2 mm screen and add to the    granulate from step d)-   f) Blend the mixture from step e) for 5 minutes using a suitable    mixer-   e) Compress the mixture from step f) using a suitable tablet press    to produce tablets with a target weight of 650 mg with each tablet    containing approximately 500 mg of paracetamol and 90 mg of niflumic    acid.

1. A pharmaceutical composition for oral administration comprising 50mg/kg paracetamol and 62.5 mg/kg niflumic acid or a pharmaceuticallyacceptable salt or ester thereof, and a pharmaceutically acceptableexcipient wherein said composition is prepared in an oral dosage form.2. A composition according to claim 1 in the form of a tablet orcapsule.